PURPOSE OF REVIEW: This review critically evaluates recent
studies investigating the effects of fatty acids on immune and inflammatory
responses in both healthy individuals and in patients with inflammatory
diseases, with some reference to animal studies where relevant. It examines
recent findings describing the cellular and molecular basis for the modulation
of immune function by fatty acids. The newly emerging area of diet-genotype
interactions will also be discussed, with specific reference to the
anti-inflammatory effects of fish oil. RECENT FINDINGS: Fatty acids are
participants in many intracellular signalling pathways. They act as ligands for
nuclear receptors regulating a host of cell responses, they influence the
stability of lipid rafts, and modulate eicosanoid metabolism in cells of the
immune system. Recent findings suggest that some or all of these mechanisms may
be involved in the modulation of immune function by fatty acids. SUMMARY: Human
studies investigating the relationship between dietary fatty acids and some
aspects of the immune response have been disappointingly inconsistent. This
review presents the argument that most studies have not been adequately powered
to take into account the influence of variation (genotypic or otherwise) on
parameters of immune function. There is well-documented evidence that fatty
acids modulate T lymphocyte activation, and recent findings describe a range of
potential cellular and molecular mechanisms. However, there are still many
questions remaining, particularly with respect to the roles of nuclear
receptors, for which fatty acids act as ligands, and the modulation of
eicosanoid synthesis, for which fatty acids act as precursors.

Eicosapentaenoic acid (EPA) is an omega-3 polyunsaturated
fatty acid that plays an important role in the regulation of biological
functions and prevention and treatment of a number of human diseases such as
heart and inflammatory diseases. As fish oil fails to meet the increasing demand
for purified EPA, alternative sources are being sought. Microalgae contain large
quantities of high-quality EPA and they are considered a potential source of
this important fatty acid. Some microalgae can be grown heterotrophically on
cheap organic substrate without light. This mode of cultivation can be well
controlled and provides the possibility to maximize EPA production on a large
scale. Numerous strategies have been investigated for commercial production of
EPA by microalgae. These include screening of high EPA-yielding microalgal
strains, improvement of strains by genetic manipulation, optimization of culture
conditions, and development of efficient cultivation systems. This paper reviews
recent advances in heterotrophic production of EPA by microalgae with an
emphasis on the use of diatoms as producing organisms.

Plant-derived alpha-linolenic acid has been studied in a
limited number of investigations. So far, some epidemiologic and a few
mechanistic studies suggest a potential of protection from cardiovascular
disease, but this potential remains to be proven in intervention studies. In
contrast, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are
prevalent in fish and fish oils, have been studied in thousands of
investigations. A consistent body of evidence has been elaborated in various
types of investigations, ultimately demonstrating reduction in total mortality,
cardiovascular mortality, and morbidity by ingestion of roughly 1 g/d of EPA
plus DHA. Current guidelines, however, do not discern between the omega-3 fatty
acids mentioned; in fact, most even do not differentiate polyunsaturated fatty
acids at all. Unfortunately, this complicates efficient implementation of an
effective means of prophylaxis of atherosclerosis.

This overview assesses the effectiveness of nutritional
interventions to prevent or treat maternal morbidity, mortality and preterm
delivery. Cochrane systematic reviews and other up-to-date systematic reviews
and individual randomized controlled trials were sought. Searches were carried
out up to July 2002. Iron and folate supplements reduce anemia and should be
included in antenatal care programs. Calcium supplementation to women at high
risk of hypertension during pregnancy or low calcium intake reduced the
incidence of both preeclampsia and hypertension. Fish oil and vitamins E and C
are promising for preventing preeclampsia and preterm delivery and need further
testing. Vitamin A and beta-carotene reduced maternal mortality in a large
trial; ongoing trials should provide further evaluation. No specific nutrient
supplementation was identified for reducing preterm delivery. Nutritional
advice, magnesium, fish oil and zinc supplementation appear promising and should
be tested alone or together in methodologically sound randomized controlled
trials. Anema in pregnancy can be prevented and treated effectively. Considering
the multifactorial etiology of the other conditions evaluated, it is unlikely
that any specific nutrient on its own, blanket interventions or magic bullets
will prevent or treat preeclampsia, hemorrhage, obstructed labor, infections,
preterm delivery or death during pregnancy. The few promising interventions for
specific outcomes should be tested or reconsidered when results of ongoing
trials become available. Until then, women and their families should receive
support to improve their diets as a general health rule, which is a basic human
right.

A literature review on fish oil supplementation in the
population undergoing chronic hemodialysis therapy suggests that supplementation
may be beneficial for various challenges to health and well-being prevalent in
this population. One study indicated that pruritus symptoms improved with fish
oil supplementation, but not with supplementation with two other oils. In a
study designed to determine whether fish oils could prevent vascular access
graft thrombosis, graft patency rates were approximately 76% in the fish oil and
approximately 15% in the placebo group (P>.03). In a pilot study, subjects given
fish oil required 16% less erythropoietin and experienced a 3.6% increase in
serum albumin levels. Some studies suggest that fish oil supplementation in
hemodialysis patients is cardioprotective, with one study finding that "fish
eaters" are half as likely to die as "non-fish eaters." Potential risks of
supplementation include gastrointestinal distress, prolonged bleeding, and
vitamin A toxicity, although the likelihood of serious side effects is probably
low. Dietitians are in a position to advise physicians and/or patients regarding
appropriate dosages and ways to minimize risks when supplementation seems
warranted. Future research could compare the benefits of fish consumption with
those of fish oil supplementation and explore the benefits of other n-3 fatty
acid sources, such as flaxseed.

Fish oil consumption may help to normalize the prethrombotic
state and reduce arterial disease. This antithrombotic potential of fish oil,
rich in (n-3) polyunsaturated fatty acids (PUFA), has been attributed to a
reduction in platelet activation, a lowering of plasma triglycerides and
(vitamin K-dependent) coagulation factors and/or a decrease in vascular tone.
Most intervention studies have shown only moderate effects of (n-3) PUFA on
these hemostatic variables. On the other hand, the usually small prolongation in
bleeding time with fish oil does not appear to lead to bruising or hemorrhage,
at least in healthy subjects. This contrasts with the increased bleeding risk
accompanying the more prominent antihemostatic effects of antiplatelet and
anticoagulant drugs. Here we propose that the beneficial effect of (n-3) PUFA
diet is related to down-regulation of the mutually positive interactions of
platelet activation and coagulation. In addition, we consider the possibility
that the dietary effect on hemostatic and lipid factors involves transcription
regulation of multiple genes, perhaps in a subject-dependent manner.

This article presents the literature materials about
polyunsaturated fatty acids as nutritional immunomodulators.

Terry, P. D., T. E. Rohan, et al. (2003).
"Intakes of fish and marine fatty acids and the risks of cancers of the breast
and prostate and of other hormone-related cancers: a review of the epidemiologic
evidence." Am J Clin Nutr77(3): 532-43.

Marine fatty acids, particularly the long-chain
eicosapentaenoic and docosahexaenoic acids, have been consistently shown to
inhibit the proliferation of breast and prostate cancer cell lines in vitro and
to reduce the risk and progression of these tumors in animal experiments.
However, whether a high consumption of marine fatty acids can reduce the risk of
these cancers or other hormone-dependent cancers in human populations is
unclear. Focusing primarily on the results of cohort and case-control studies,
we reviewed the current epidemiologic literature on the intake of fish and
marine fatty acids in relation to the major hormone-dependent cancers. Despite
the many epidemiologic studies that have been published, the evidence from those
studies remains unclear. Most of the studies did not show an association between
fish consumption or marine fatty acid intake and the risk of hormone-related
cancers. Future epidemiologic studies will probably benefit from the assessment
of specific fatty acids in the diet, including eicosapentaenoic and
docosahexaenoic acids, and of the ratio of these to n-6 fatty acids, dietary
constituents that have not been examined individually very often.

Spector, S. L. and M. E. Surette (2003). "Diet
and asthma: has the role of dietary lipids been overlooked in the management of
asthma?" Ann Allergy Asthma Immunol90(4): 371-7; quiz 377-8, 421.

OBJECTIVE: This article discusses the role of diet in the
management of asthma. Readers will gain an understanding of how evolution of the
western diet has contributed to increased asthma prevalence and how dietary
modification that includes management of dietary lipids may reduce symptoms of
asthma. DATA SOURCES: Relevant studies published in English were reviewed. STUDY
SELECTION: Medline search to identify peer-reviewed abstracts and journal
articles. RESULTS: Asthma and obesity, which often occur together, have
increased in prevalence in recent years. Studies suggest adaption of a western
diet has not only contributed to obesity, but that increased intake of specific
nutrients can cause changes in the frequency and severity of asthma. Increased
asthma prevalence has also been proposed to arise from increased exposure to
diesel particles or lack of exposure to infectious agents or endotoxins during
childhood, generating a biased Th2 immune response, and increased cytokine and
leukotriene production. Antagonists directed against these pro-inflammatory
mediators include anticytokines and antileukotrienes. A reduction in the levels
of inflammatory mediators associated with asthma has also been seen with dietary
interventions, such as the administration of oils containing gamma-linolenic
acid and eicosapentaenoic acid. CONCLUSIONS: Evidence suggests elevated body
mass index and dietary patterns, especially intake of dietary lipids, contribute
to symptoms of asthma. Dietary modification may help patients manage their
asthma as well as contribute to their overall health.

Consumption of fish and fish oils was first associated with
decreased risk of cardiovascular disease almost 50 years ago. Since then, a
number of epidemiologic studies have evaluated whether their consumption is
specifically associated with stroke. Ecologic/cross-sectional and case-control
studies have generally shown an inverse association between consumption of fish
and fish oils and stroke risk. Results from five prospective studies have been
less consistent, with one showing no association, one showing a possible inverse
association, and three demonstrating a significant inverse association. In the
latest and largest of these, the Nurses Health Study, the relative risk of total
stroke was lower, although not significantly so, among women who regularly ate
fish than among those who did not. A significant decrease in the risk of
thrombotic stroke (relative risk, 0.49; 95% confidence interval, 0.26-0.93) was
observed among women who ate fish at least two times per week compared with
women who ate fish less than once per month, after adjustment for age, smoking,
and other cardiovascular risk factors; a nonsignificant decrease was observed
among women in the highest quintile of long-chain omega-3 polyunsaturated fatty
acid intake. No association was observed between consumption of fish or fish oil
and hemorrhagic stroke. These data support the hypothesis that consumption of
fish several times per week reduces the risk of thrombotic stroke but does not
increase the risk of hemorrhagic stroke.

INTRODUCTION: Hyperlipoproteinemia is a key factor in
development of atherosclerosis, whereas regression of atherosclerosis mostly
depends on decreasing the plasma level of total and LDL-cholesterol. Many
studies have reported the hypocholesterolemic effect of linolenic acid. TYPES OF
POLYUNSATURATED FATTY ACIDS (PUFA): Linoleic and alpha-linolenic acids are
essential fatty acids. The main sources of linoleic acid are vegetable seeds and
of alpha-linolenic acid-green parts of plants. alpha-linolenic acid is converted
to eicosapentaenoic and docosahexaenoic acid. Linoleic acid is converted into
arachidonic acid competing with eicosapentaenoic acid in the starting point for
synthesis of eicosanoids, which are strong regulators of cell functions and as
such, very important in physiology and pathophysiology of cardiovascular system.
Eicosanoids derived from eicosapentaneoic acid have different biological
properties in regard to those derived from arachidonic acid, i.e. their global
effects result in decreased vasoconstriction, platelet aggregation and leukocyte
toxicity. ROLE AND SIGNIFICANT OF PUFA: The n-6 to n-3 ratio of polyunsaturated
fatty acids in the food is very important, and an optimal ratio 4 to 1 in diet
is a major issue. Traditional western diets present absolute or relative
deficiency of n-3 polyunsaturated fatty acids, and a ratio 15-20 to 1. In our
diet fish and fish oil are sources of eicosapentaenoic and docosahexaenoic acid.
Refined and processed vegetable oils change the nature of polyunsaturated fatty
acids and obtained derivates have atherogenic properties.

Dyslipidemic conditions and their cardiovascular related
complications are common. Effective primary and secondary prevention strategies
include therapies to lower LDL and total cholesterol and to increase HDL.
Further, it seems that there is a need for therapeutic reduction in
triglycerides as it emerges as an independent risk factor for CVD. Many clinical
trials have been designed to evaluate pharmacologic compounds in the treatment
of the dyslipidemias and they seem to have shown a safe profile, both in the
experiment phases and in post-marketing observation studies. Nevertheless,
sporadic reports of hepatotoxicity with statins and niacin still arise (Table
2). Although routine hepatic biochemical test monitoring is recommended, the
cost-effectiveness is questionable because often these reactions are
idiosyncratic and may not be identified by this routine screening. The
risk/benefit ratio is in favor of using these medications in individuals at
risk. There is no evidence to suggest intrinsic hepatotoxic activity as such.
Drugs that lower triglycerides such as fibrates, have been observed to improve
hepatic biochemical tests, although in small series. This leads to speculation
whether treatment with fibrates would be beneficial for non-alcoholic fatty
liver disease (NAFLD), a condition that is emerging as one of enormous
magnitude.

Exercise-induced asthma (EIA) occurs in up to 90% of
individuals with asthma and approximately 10% of the general population without
asthma. EIA describes a condition in which vigorous physical activity triggers
acute airway narrowing with heightened airway reactivity resulting in reductions
in forced expiratory volume in 1 second of greater than 10% compared with
pre-exercise values. Treatment of EIA almost exclusively involves the use of
pharmacological medications. However, there is accumulating evidence that a
dietary excess of salt and omega-6 fatty acids, and a dietary deficiency of
antioxidant vitamins and omega-3 fatty acids, can modify the severity of EIA.
The modification of these dietary factors has the potential to reduce the
incidence and prevalence of this disease. The dietary component most studied to
date is dietary salt. Recent studies have supported a role for dietary salt as a
modifier of the severity of EIA, suggesting that salt-restrictive diets can
reduce the severity of EIA. Since EIA is part of the asthmatic diathesis, it is
possible that EIA may serve as a useful model for investigation of potential
dietary interventions for reducing airway hyperresponsiveness.

Lee, K. W. and G. Y. Lip (2003). "The role of
omega-3 fatty acids in the secondary prevention of cardiovascular disease."
Qjm96(7): 465-80.

It has long been recognized from epidemiological studies that
Greenland Eskimos have substantially reduced rates of acute myocardial
infarction (MI) compared with Western controls. From these epidemiological
observations, the benefits of fatty fish consumption have been explored in cell
culture and animal studies, as well as randomized controlled trials
investigating the cardioprotective effects of omega-3 fatty acids. Dietary
omega-3 fatty acids seem to stabilize the myocardium electrically, resulting in
reduced susceptibility to ventricular arrhythmias, thereby reducing the risk of
sudden death. These fatty acids also have potent anti-inflammatory effects, and
may also be antithrombotic and anti-atherogenic. Furthermore, the recent GISSI-Prevention
study of 11 324 patients showed a marked decrease in risk of sudden cardiac
death as well as a reduction in all-cause mortality in the group taking a highly
purified form of omega-3 fatty acids, despite the use of other secondary
prevention drugs, including beta-blockers and lipid-lowering therapy. The use of
omega-3 fatty acids should be considered as part of a comprehensive secondary
prevention strategy post-myocardial infarction.

This is a review of our present understanding of the
mechanism by which the n-3 polyunsaturated fatty acids (PUFA) in fish oils
prevent fatal ventricular arrhythmias in animals and cultured heart cells. A
brief review of three clinical trials that suggest that these PUFAs prevent
sudden cardiac death is also included in order to emphasize the potential
importance of these fatty acids in human nutrition. The PUFAs act by stabilizing
electrically every cardiac myocyte by modulating conductance of ion channels in
the sarcolemma, particularly the fast, voltage-dependent sodium current and the
L-type calcium currents, though other ion currents are also affected. Work in
progress suggests that the primary site of action of the PUFAs may be on the
phospholipid bilayer of the heart cells in the microdomains through which the
ion channels penetrate the membrane bilayer in juxtaposition with the ion
channels rather than directly on the channel protein itself. These PUFAs then
allosterically alter the conformation and conductance of the channels. Both
potential benefits and possible adverse effects of the PUFAs in man will be
discussed. Knowing that the ion channels have been structurally conserved among
all excitable tissues, we tested their effects on the electrophysiology of rat
hippocampal CA1 neurons and found that the sodium and calcium ion channels in
these neurons were also affected by PUFAs. An attempt to show the place of the
PUFAs in human nutrition during the 2-4 million years of our evolution will
conclude the review.

Polyunsaturated fatty acids (PUFAs), such as docosahexaenoic
acid (DHA), are natural constituents of the human diet; however, dietary intakes
of these fatty acids are below recommended values. The main dietary source of
DHA is fatty fish, with lesser amounts provided by shellfish, marine mammals,
and organ meats. The addition to traditional food products of refined oils
produced by marine microalgae represents potential sources of supplemental
dietary DHA. DHA45-oil is manufactured through a multi-step fermentation and
refining process using a non-toxigenic and non-pathogenic marine protist.
Comprising approximately 45% DHA, and lesser concentrations of palmitic acid and
docosapentaenoic acid, DHA45-oil is intended for use in foods as a dietary
source of DHA. The safety of DHA45-oil was evaluated in various genotoxicity and
acute, subchronic, and reproductive toxicity studies. DHA45-oil produced
negative results in genotoxicity assays and demonstrated a low acute oral
toxicity in mice and rats. Dietary administration of DHA45-oil to rats in
subchronic and one-generation reproductive studies produced results consistent
with those observed in oral studies using high concentrations of omega-3 PUFAs
from fish or other microalgal-derived oils. The results of these studies, as
well as those of various published metabolic, toxicological, and clinical
studies with DHA-containing oils, support the safety of DHA45-oil as a potential
dietary source of DHA.

For most patients who require lipid-lowering treatment,
statin monotherapy is the appropriate treatment. However, in those patients
where statin monotherapy does not produce optimal lipid levels, the combination
of a statin with niacin, a bile acid sequestrant, a fibric acid derivative, a
cholesterol absorption inhibitor or a fish oil preparation may provide improved
control. The choice of combination therapy depends upon the patient's lipid
profile and tolerability of the medication. Combination of a statin with niacin,
a bile acid sequestrant or ezetimibe, a cholesterol absorption inhibitor, should
be considered for patients with very high low-density lipoprotein cholesterol (LDL-C)
levels, while combination with either a fibric acid derivative or a fish oil
should be considered for patients with high LDL-C and high triglyceride levels.
A number of new lipid-lowering agents are currently in development, including
cholesteryl ester transfer protein (CETP) inhibitors, acyl coenzyme A:
cholesterol acyltransferase (ACAT) inhibitors, ileal bile acid transport (IBAT)
inhibitors, microsomal triglyceride transfer protein (MTP) inhibitors and dual
peroxisome proliferator-activated receptor (PPAR) alpha and gamma agonists.
Introduction of these novel therapies will provide opportunities for developing
different combination strategies that may help to optimise lipid profiles in
patients who are currently difficult to treat. The introduction of new
combinations will require careful study to ensure that the risks of drug
interactions and adverse events are minimised.

The modification of dietary fat in the diet of diabetic
patients is of interest with respect to metabolic and other consequences of this
modification. To begin with the data are reviewed for the use of monounsaturated
fatty acids (MUFA) in the diabetes diet. Compared to a carbohydrate-rich diet,
glucose concentrations are lower. Blood pressure was also found to be lower.
There were no major differences with respect to lipid concentrations. HDL-cholesterol
levels tended to be higher after a MUFA-rich diet. In type-1 diabetic patients,
the number of circulating big VLDL particles was greater after a MUFA diet than
after a carbohydrate-rich diet. Comparisons were also made between diets
enriched with MUFA and with polyunsaturated fatty acids (PUFA). With respect to
lipid concentrations, different groups observed different effects. While one
group saw no differences in fasting lipids, they measured a higher remnant-like
particle cholesterol after a diet enriched with MUFA. Another group found higher
total and LDL-cholesterol levels after a PUFA-rich diet than after a MUFA-diet.
In their study, fasting glucose, insulin and fasting chylomicrons and
postprandial chylomicrons and VLDL were higher following the PUFA diet. A MUFA-rich
diet increased endothelium-dependent flow-mediated dilatation in the superficial
femoral artery. Alpha-linolenic acid appears to be a precursor of
eicospentaenoic and docosahexaenoic fatty acids. As a diet rich in n-6 PUFA
reduces this conversion, a n-6/n-3 PUFA ratio not exceeding 4 - 6 should be
observed. No prospective data are available for alpha-linolenic acid in diabetic
patients. The review summarizes the results of the Lyon Diet Heart Study and the
Nurses' Health Study. Both studies saw a reduced cardiovascular risk associated
with a higher intake of alpha-linolenic acid. Finally, data on the effects of
fish oil are given. The latter has a clearly expressed triglyceride-lowering
effect. Data with respect to glucose control are heterogeneous. Major studies
did not find any influence in glucose concentrations. Hepatic glucose production
and peripheral insulin sensitivity remained constant. Evidently, nerve function
can be improved by fish oil. Data have been compiled comparing the effects of
fish oil with those of olive oil, linseed oil and sunflower oil.

BACKGROUND: Limited evidence supports a hypothesis suggesting
that schizophrenic symptoms may be the result of altered neuronal membrane
structure and metabolism. This structure and metabolism is dependent on blood
plasma levels of certain essential fatty acids and their metabolites.
OBJECTIVES: To review the effects polyunsaturated fatty acids for people with
schizophrenia. SEARCH STRATEGY: The initial search of 1998 was updated. We
searched the Cochrane Schizophrenia Group's Register (July 2002), and authors of
included studies and relevant pharmaceutical companies were contacted. SELECTION
CRITERIA: All randomised clinical trials of polyunsaturated fatty acid treatment
for schizophrenia. DATA COLLECTION AND ANALYSIS: Reviewers, working
independently, selected, quality assessed, and extracted relevant data. Analysis
was on an intention-to-treat basis. Where possible and appropriate Relative Risk
(RR) and their 95% confidence intervals (CI) were calculated and the number
needed to treat (NNT) estimated. For continuous data, weighted mean differences
(WMD) and their 95% confidence intervals were calculated. Data were inspected
for heterogeneity. MAIN RESULTS: Five short small studies (n=313) were included.
One small study (n=30) suggested that an omega-3 EFA (ecisapentenoic acid (EPA)
enriched oil) may have some antipsychotic properties when compared with placebo,
even if not given as a supplement to standard drugs (RR not needing
antipsychotic drugs 0.73 CI 0.54 to 1.00; RR less than 25% improvement in PANSS
0.54 CI 0.3 to 0.96, NNT 3 CI 2 to 29). Other studies comparing omega-3 EFA's
with placebo as a supplement to antipsychotics were too small to be conclusive.
There was a suggestion that people already on antipsychotics when given omega-3
EFA supplementation had greater improvement of mental state compared to those
receiving a placebo supplementation but the result were not significant (n=29, 1
RCT, RR <25% improvement in PANSS 0.62 CI 0.37 to 1.05). However, the mental
state of both medicated and un-medicated patients was significantly better for
those receiving omega-3 EFA supplementation (n=59, 2 RCTs, RR <25% improved on
PANSS 0.58 CI 0.39 to 0.85, NNT 3 CI 2-8). Medium term data, however, did not
favour either group (n=87, 1 RCT, MD PANSS endpoint -1.0 CI -8.15 to 6.15). All
studies had low attrition (<10% total, n=271, 4 RCTs, RR leaving the study early
0.91 CI 0.36 to 2.33). Another study (n=31) comparing two types of omega-3 EFA's,
ecisapentenoic acid enriched oil and docosahexanoic acid oil, also found no
differences between these two EFA's in measures of mental state. One small
(n=16) study investigated the effects of an omega-6 EFA compared with placebo
for tardive dyskinesia and found no clear effects. There is not a clear dose
response to omega-3 supplementation. Adverse effects seem rare but diarrhoea may
be a problem in the medium term. REVIEWER'S CONCLUSIONS: The use of omega-3
polyunsaturated fatty acids for schizophrenia remains experimental and large
well designed, conducted and reported studies are indicated and needed.

Largely initiated by studies among Eskimos in the early
1970s, great attention has been given to possible effects of omega-3
polyunsatured fatty acids (PUFA) in cardiovascular diseases. A series of
positive effects on pathogenetic mechanisms of cardiovascular disease has been
discovered from laboratory studies in cell cultures, animal models and in
humans. omega-3 PUFA can reduce platelets and leucocytes activities as well as
plasma triglycerides. Moreover they can have antiarrhythmic properties. Nowadays
patients who experienced myocardial infarction have decreased risk of total and
cardiovascular mortality by treatment with omega-3 PUFA (1 g daily). This effect
is present irrespective of high or low fish intake or simultaneous intake of
other drugs for secondary prevention of coronary heart disease. Mainly on the
basis of GISSI Prevention trial results, dietary supplementation with omega-3
PUFA is now recommended as a new component of secondary prevention after
myocardial infarction in national and international guidelines.

Malnutrition is prevalent in patients with cancer. This can
have deleterious effects including reduced response to treatment, diminished
quality of life, increased length of hospital stay and decreased survival. It
is, therefore, imperative that thorough nutritional screening is carried out by
nurses on patients' admission and during their hospital stay to detect those who
are malnourished or at risk of malnutrition in order to plan their nutritional
care effectively. Cancer cachexia is the progressive weight loss and emaciation
seen in cancer patients, particularly in advanced disease, which can have a
devastating effect on the physical, psychological, social and spiritual aspects
of the patient's life. Therefore, the aims of nutritional care are identified
depending on the stage of the patient's illness and recommendations made for
nursing, pharmacological and nutritional intervention. These include nursing
comfort strategies, the use of recommended pharmacological agents and dietary
interventions such as experimenting with different foods, textures, portion
sizes and nutritional supplements. The use of fish oil-enhanced nutritional
supplements and artificial nutritional support is also discussed. Consideration
is also given to the legal and ethical aspects of providing nutrition and
nutritional support.

Cell membranes are not simply barriers separating
intracellular from extracellular space. Rather, they represent a dynamic
high-turnover system that adapts to current demands. During inflammation,
prostaglandins and leukotrienes are formed from membrane-derived phospholipids.
Encouraging improvements in critically ill patients were observed after
nutritional replacement of long-chain omega-6 fatty acids with long-chain
omega-3-fatty acids, contained in fish oil.

Dietary supplements are used by more than one-half of the
adult US population. In contrast to pharmaceuticals, dietary supplements may be
sold in the United States with little regulation other than listing of
ingredients and the potential health benefits. By contrast, herbal products in
Germany are carefully regulated by the same standards as drugs, and efforts are
under way to standardize their regulation in the entire European Union. Most
herbal users do not inform their physicians that they are taking these
supplements, and most physicians do not inquire. Although some herbal products
have clinically proven benefits, it is increasingly apparent that many contain
potentially toxic substances, particularly in relation to interactions with
drugs. Hence, it is essential that practicing physicians develop a working
knowledge of herbals-specifically, about claims for their usage and potential or
proven efficacies and toxicities-and that they incorporate such knowledge into
the evaluation and management of their patients. By contrast, functional
foods-integral components of the diet that are understood to contribute added
health benefits-are the subject of intense and widespread research in food and
nutritional science. Examples include many polyphenolic substances, carotenoids,
soy isoflavones, fish oils, and components of nuts that possess antioxidant and
other properties that decrease the risk of vascular diseases and cancer.
Practicing physicians are advised to stay abreast of these emerging findings in
order to best advise their patients on the value of health-promoting diets in
disease prevention.

Many healthy subjects and patients are taking natural
bioactive products for the prevention and treatment of multiple conditions,
including gastrointestinal disorders. Based on current evidence, the scientific
validity of the use of many of these commercial compounds by the general public
is severely limited, with quality control and regulatory issues continuing to be
a concern. Nevertheless, there is sufficient preliminary data to warrant further
research of these products in order to identify novel compounds for potential
clinical use in addition to performing formal randomized controlled clinical
trials of the commercial preparations.

PURPOSE: Complementary and alternative medicine (CAM)
therapies are widely used in the general population. This paper reviews
randomized controlled trials of CAM therapies for obstetrical and gynecologic
conditions and presents therapies that are likely to be used by women of
reproductive age and by pregnant women. DATA SOURCES: Sources included
English-language papers in MEDLINE 1966-2002 and AMED (1985-2000) and the
authors' extensive holdings. STUDY SELECTION: Randomized controlled clinical
trials of CAM therapies for obstetric and gynecologic conditions. DATA
EXTRACTION: Clinical information was extracted from the articles and summarized
in tabular form or in the text.DATA SYNTHESIS: Ninety-three trials were
identified, 45 of which were for pregnancy-related conditions, 33 of which were
for premenstrual syndrome, and 13 of which were for dysmenorrhea. Data support
the use of acupressure for nausea of pregnancy and calcium for PMS. Preliminary
studies indicate a role for further research on Vitamin B6 or ginger for nausea
and vomiting of pregnancy; calcium, magnesium, Vitamin B6, or chaste-tree berry
extract for PMS; and a low-fat diet, exercise, or fish oil supplementation for
dysmenorrhea. CONCLUSIONS: Limited evidence supports the efficacy of some CAM
therapies. Exposure of women of reproductive age to these therapies can be
expected.

There is now a large number of potential immunomodulatory
agents that may be of value in inflammatory bowel disease. The newer
immunosuppressants, such as tacrolimus and mycophenolate, probably offer little
more than providing comparable alternatives to more established agents, and fish
oil and other eicosanoid modulators are probably not especially potent if
effective. The biological agents, however, bring a more novel and potentially
powerful approach. Natalizumab, and targeted mucosal delivery of interleukin-10
already show considerable promise.

Diet has traditionally played an important role in diabetic
therapy. Over the years, various diets have been proposed, often without
scientific evidence. One of the main errors was (is) to speculate that there
exists a direct linear correlation between the injection of x units of insulin
and the utilization of y grams of glucose. If this were true, one should give
more insulin to practice physical activity. In reality, it is the reverse.
Dietary recommendations issued over the last few years are the same for diabetic
and non-diabetic individuals in order to avoid degenerative diseases. In many
countries, the intake of fat is too high, and that of complex carbohydrates too
low. The so-called 'Mediterranean diet', in combination with appropriate insulin
therapy, may be optimal. This consists mainly of fiber-rich complex
carbohydrates (grain), vegetables, fruits, fish, and olive oil. Explanations of
this diet should focus on quality rather than quantity of foodstuffs, and should
be given by a multidisciplinary team. Prescription of a highly rigid diet has
proved ineffective in producing adequate metabolic control, and increases the
risk of deviations from the diet. In our experience, the proper use of the
two-injection regimen, in countries where the meal schedule allows correct
allocation of diet, may lead to 'intensive conventional therapy' and good
metabolic control. It is inadequate to systematically assign the
multiple-insulin injection regimen to intensified insulin therapy, and the
'conventional' two-injection regimen to a non-intensified insulin therapy. The
proper use of the basal-bolus regimen, with increased flexibility in daily life
and dietary freedom, cannot always be applied successfully before adolescence.
The adjustment of insulin dosage is more complicated than in the twice-daily
injection regimen because dose alteration cannot be made only according to
sliding scales based on the glycemia measured immediately before the insulin
injection. The simplistic use of these non-physiological sliding scales is the
main error in the multiple daily insulin injection regimen. The use of
fast-acting insulin analogs in the basal-prandial regimen improves post-prandial
glycemia at the expense of an increase in pre-prandial glucose levels, if the
period between two meals, and therefore two injections, exceeds 3-4 hours,
because of the short duration of action. If there are 4-6 or 7 hours between two
meals, it is better to use a rapid-acting insulin. Avoid dogmatism--only
objective results (good glycosylated hemoglobin and lipid levels, as well as
good quality of life) are important.

The Apc(Min/+) mouse model and the azoxymethane (AOM) rat
model are the main animal models used to study the effect of dietary agents on
colorectal cancer. We reviewed recently the potency of chemopreventive agents in
the AOM rat model (D. E. Corpet and S. Tache, Nutr. Cancer, 43: 1-21, 2002).
Here we add the results of a systematic review of the effect of dietary and
chemopreventive agents on the tumor yield in Min mice. The review is based on
the results of 179 studies from 71 articles and is displayed also on the
internet http://corpet.net/min.(2) We compared the efficacy of agents in the Min
mouse model and the AOM rat model, and found that they were correlated (r =
0.66; P < 0.001), although some agents that afford strong protection in the AOM
rat and the Min mouse small bowel increase the tumor yield in the large bowel of
mutant mice. The agents included piroxicam, sulindac, celecoxib,
difluoromethylornithine, and polyethylene glycol. The reason for this
discrepancy is not known. We also compare the results of rodent studies with
those of clinical intervention studies of polyp recurrence. We found that the
effect of most of the agents tested was consistent across the animal and
clinical models. Our point is thus: rodent models can provide guidance in the
selection of prevention approaches to human colon cancer, in particular they
suggest that polyethylene glycol, hesperidin, protease inhibitor, sphingomyelin,
physical exercise, epidermal growth factor receptor kinase inhibitor, (+)-catechin,
resveratrol, fish oil, curcumin, caffeate, and thiosulfonate are likely
important preventive agents.

Polyunsatured fatty acids are made out of a hydrocarbonated
chain of variable length with several double bonds. The position of the first
double bond (omega) differentiates polyunsatured omega 3 fatty acids (for
example: alpha-linolenic acid or alpha-LNA) and polyunsatured omega 6 fatty
acids (for example: linoleic acid or LA). These two classes of fatty acids are
said to be essential because they cannot be synthetised by the organism and have
to be taken from alimentation. The omega 3 are present in linseed oil, nuts,
soya beans, wheat and cold water fish whereas omega 6 are present in maize,
sunflower and sesame oil. Fatty acids are part of phospholipids and,
consequently, of all biological membranes. The membrane fluidity, of crucial
importance for its functioning, depends on its lipidic components. Phospholipids
composed of chains of polyunsatured fatty acids increase the membrane fluidity
because, by bending some chains, double bonds prevent them from compacting
themselves perfectly. Membrane fluidity is also determined by the
phospholipids/free cholesterol ratio, as cholesterol increases membrane
viscosity. A diet based on a high proportion of essential polyunsatured fatty
acids (fluid) would allow a higher incorporation of cholesterol (rigid) in the
membranes to balance their fluidity, which would contribute to lower blood
cholesterol levels. Brain membranes have a very high content in essential
polyunsatured fatty acids for which they depend on alimentation. Any dietary
lack of essential polyunsatured fatty acids has consequences on cerebral
development, modifying the activity of enzymes of the cerebral membranes and
decreasing efficiency in learning tasks. EPIDEMIOLOGICAL DATA: The prevalence of
depression seems to increase continuously since the beginning of the century.
Though different factors most probably contribute to this evolution, it has been
suggested that it could be related to an evolution of alimentary patterns in the
Western world, in which polyunsatured omega 3 fatty acids contained in fish,
game and vegetables have been largely replaced by polyunsatured omega 6 fatty
acids of cereal oils. Some epidemiological data support the hypothesis of a
relation between lower depression and/or suicide rates and a higher consumption
of fish. These data do not however prove a relation of causality. CHOLESTEROL
AND DEPRESSION: Several cohort studies (on nondepressed subjects) have assessed
the relationship between plasma cholesterol and depressive symptoms with
contradictory results. Though some results found a significant relationship
between a decrease of total cholesterol and high scores of depression, some
other did not. Studies among patients suffering from major depression signalled
more constantly an association between low cholesterol and major depression.
Besides, some trials showed that clinical recovery may be associated with a
significant increase of total cholesterol. CHOLESTEROL AND SUICIDAL BEHAVIOR:
The hypothesis that a low cholesterol level may represent a suicidal risk factor
was discovered accidentally following a series of epidemiological studies which
revealed an increase of the suicidal risk among subjects with a low cholesterol
level. Though some contradictory studies do exist, this relationship has been
confirmed by several subsequent cohort studies. These findings have challenged
the vast public health programs aimed at promoting the decrease of cholesterol,
and even suggested to suspend the administration of lipid lowering drugs. Recent
clinical studies on populations treated with lipid lowering drugs showed
nevertheless a lack of significant increase of mortality, either by suicide or
accident. In addition, several controlled studies among psychiatric patients
revealed a decrease of the concentrations of plasma cholesterol among patients
who had attempted suicide in comparison with other patients. POLYUNSATURATED
FATTY ACID AND DEPRESSION: In major depression, all studies revealed a
significant decrease of the polyunsaturated omega 3 fatty acids and/or an
increase of the omega 6/omega 3 ratio in plasma and/or in the membranes of the
red cells. In addition, two studies found a higher severity of depression when
the level of polyunsaturated omega 3 fatty acids or the ratio omega 3/omega 6
was low. Parallel to these modifications, other biochemical perturbations have
been reported in major depression, particularly an activation of the
inflammatory response system, resulting in an increase of the pro-inflammatory
cytokines (interleukins: IL-1b, IL-6 and interferon g) and eicosanoids (among
others, prostaglandin E2) in the blood and the CSF of depressed patients. These
substances cause a peroxidation and, consequently a catabolism of membrane
phospholipids, among others those containing polyunsaturated fatty acids. The
cytokines and eicosanoids derive from polyunsaturated fatty acids and have
opposite physiological functions according to their omega 3 or omega 6
precursor. Arachidonic acid (omega 6) is, among others, precursor of
pro-inflammatory prostaglandin E2 (PGE2), whereas polyunsaturated omega 3 fatty
acids inhibit the formation of PGE2. It has been shown that a dietary increase
of polyunsaturated omega 3 fatty acids reduced strongly the production of IL-1
beta, IL-2, IL-6 and TNF-alpha (tumor necrosis factor-alpha). In contrast, diets
with a higher supply of linoleic acid (omega 6) increased significantly the
production of pro-inflammatory cytokines, like TNF-alpha. Therefore,
polyunsaturated omega 3 fatty acids could be associated at different levels in
the pathophysiology of major depression, on the one hand through their role in
the membrane fluidity which influences diverse steps of neurotransmission and,
on the other hand, through their function as precursor of pro-inflammatory
cytokines and eicosanoids disturbing neurotransmission. In addition,
antidepressants could exhibit an immunoregulating effect by reducing the release
of pro-inflammatory cytokines, by increasing the release of endogenous
antagonists of pro-inflammatory cytokines like IL-10 and, finally, by acting
like inhibitors of cyclo-oxygenase. THERAPEUTIC USE OF FATTY ACIDS: Data
available concerning the administration of supplements of DHA (docosahexanoic
acid) or other polyunsaturated fatty acids omega 3 are limited. In a double
blind placebo-controlled study on 30 patients with bipolar disorder, the
addition of polyunsaturated omega 3 fatty acids was associated with a longer
period of remission. Moreover, nearly all the other prognosis measures were
better in the omega 3 group. Very recently, a controlled trial showed the
benefits of adding an omega 3 fatty acid, eicosopentanoic acid, among depressed
patients. After 4 weeks, six of the 10 patients receiving the fatty acid were
considered as responders in comparison with only one of the ten patients
receiving placebo. CONCLUSIONS: Some epidemiological, experimental and clinical
data favour the hypothesis that polyunsaturated fatty acids could play a role in
the pathogenesis and/or the treatment of depression. More studies however are
needed in order to better precise the actual implication of those biochemical
factors among the various aspects of depressive illness.

Fish oils are a rich source of omega-3 long chain
polyunsaturated fatty acids (n-3 LC PUFA). The specific fatty acids,
eicosapentaenoic acid and docosahexaenoic acid, are homologues of the n-6 fatty
acid, arachidonic acid (AA). This chemistry provides for antagonism by n-3 LC
PUFA of AA metabolism to pro-inflammatory and pro-thrombotic n-6 eicosanoids, as
well as production of less active n-3 eicosanoids. In addition, n-3 LC PUFA can
suppress production of pro-inflammatory cytokines and cartilage degradative
enzymes.In accordance with the biochemical effects, beneficial anti-inflammatory
effects of dietary fish oils have been demonstrated in randomised, double-blind,
placebo-controlled trials in rheumatoid arthritis (RA). Also, fish oils have
protective clinical effects in occlusive cardiovascular disease, for which
patients with RA are at increased risk.Implementation of the clinical use of
anti-inflammatory fish oil doses has been poor. Since fish oils do not provide
industry with the opportunities for substantial profit associated with patented
prescription items, they have not received the marketing inputs that underpin
the adoption of usual pharmacotherapies. Accordingly, many prescribers remain
ignorant of their biochemistry, therapeutic effects, formulations, principles of
application and complementary dietary modifications. Evidence is presented that
increased uptake of this approach can be achieved using bulk fish oils. This
approach has been used with good compliance in RA patients. In addition, an
index of n-3 nutrition can be used to provide helpful feedback messages to
patients and to monitor the attainment of target levels.Collectively, these
issues highlight the challenges in advancing the use of fish oil amid the
complexities of modern management of RA, with its emphasis on combination
chemotherapy applied early.

Dietary long chain omega-3 polyunsaturated fatty acids from
fish oil appear to be clearly efficient in regulating endothelial dysfunction
(or activation), which is the first stage of atherogenesis. Studies on
endothelial cells in vitro have shown that the main dietary PUFA and oleic acid
may prevent endothelium activation either by inhibiting the expression of
adhesion molecules or by improving the nitric oxide production. Saturated fatty
acids and also linoleic acid do not inhibit endothelium activation. The
mechanisms involved in this inhibition could be related to endothelial cell
membrane characteristics or redox status. However, these findings need to be
confirmed in vivo.

In addition to the classic soybean oil fat emulsion,
developed more than 40 years ago and still widely used, emulsions with other
lipid substrates are available today for parenteral nutrition; these substrates
implement the benefits offered by soybean oil when mixed with it in given
proportions. Soybean oil triglycerides are rich in linoleic acid, a long chain
omega-6 polyunsaturated fatty acid, which is essential and is an indispensable
component of parenteral nutrition. However, very high doses of omega-6
polyunsaturated fatty acids should be avoided, particularly in some critical
illnesses. Medium chain triglycerides, long well known to nutritionists and
dietitians for their easy intestinal absorption, have become available in
parenteral nutrition emulsions in a mixture with soybean oil. Medium chain
triglycerides are completely and readily used for energy production and do not
interfere significantly in the production of inflammatory mediators, in the
composition of cell membranes and in body organ and system functions. Omega-3
polyunsaturated fatty acids, essential fatty acids derived from fish oil,
permeate cell structure and affect cell activity with different mechanisms,
playing also an important role in the modulation of inflammatory processes.
Omega-3 emulsions in parenteral nutrition are currently added as a supplement to
other fat emulsions. Knowledge of these "non-conventional" fat emulsions is
being continuously improved by investigative work and clinical experience.

OBJECTIVE: Fish oil is a rich source of omega-3 fatty acids (FAs),
especially eicosapentaenoic acid and docosahexaenoic acid. The existing data
suggest that eicosapentaenoic acid and docosahexaenoic acid are the active
agents in fish oil. A number of clinical trials have shown that dietary fish oil
supplementation has antiatherogenic properties and immunomodulation effects.
Fish oils are not used widely in parenteral nutrition because fish oil emulsions
have not been commercially available until very recently. Studies concerning the
use of fish oil in parenteral route are rare. METHODS: We reviewed the effect of
parenteral fish oil infusion on lipid metabolism and immune response in normal
and disease conditions. RESULTS: Studies showed that the main effects of
parenteral infusion of fish oil are: 1) incorporation of omega-3 FAs into
cellular membranes of many cell populations that consequently influence the
disease process of some disease conditions, 2) an effect on eicosanoid
metabolism leading to a decrease in platelet aggregation and thrombosis, 3)
amelioration of the severity of diet-induced hepatic steatosis, 4) less
accumulation of lipid peroxidation products in liver tissue, and 5)
immunomodulation effects and therapeutic benefits in animal disease models or
various disease conditions of humans. Most of these studies suggested that
parenteral infusion of omega-3 FAs have clinical beneficial effects comparable
to those of dietary administration. However, different effects of omega-3 and
omega-6 FAs in some situations has been reported. For example, plasma
triacylglycerol levels were not lowered after fish oil infusion in normal or
diabetic rats when compared with those of safflower oil or soybean oil infusion.
The reason for the difference remain unclear. CONCLUSION: The metabolic and
immunologic effects of parenteral use of omega-3 FAs requires further
evaluation, especially in some disease conditions.

Lipids used in nutritional support of surgical or critically
ill patients have been based on soybean oil, which is rich in the n-6 fatty acid
linoleic acid (18:2n-6). Linoleic acid is the precursor of arachidonic acid
(20:4n-6). In turn, arachidonic acid in cell membrane phospholipids is the
substrate for the synthesis of a range of biologically active compounds (eicosanoids)
including prostaglandins, thromboxanes, and leukotrienes. These compounds can
act as mediators in their own right and can also act as regulators of other
processes, such as platelet aggregation, blood clotting, smooth muscle
contraction, leukocyte chemotaxis, inflammatory cytokine production, and immune
function. There is a view that an excess of n-6 fatty acids should be avoided
since this could contribute to a state where physiological processes become
dysregulated. One alternative is the use of fish oil. The rationale of this
latter approach is that fish oil contains long chain n-3 fatty acids, such as
eicosapentaenoic acid. When fish oil is provided, eicosapentaenoic acid is
incorporated into cell membrane phospholipids, partly at the expense of
arachidonic acid. Thus, there is less arachidonic acid available for eicosanoid
synthesis. Hence, fish oil decreases production of prostaglandins like PGE2 and
of leukotrienes like LTB4. Thus, n-3 fatty acids can potentially reduce platelet
aggregation, blood clotting, smooth muscle contraction, and leukocyte chemotaxis,
and can modulate inflammatory cytokine production and immune function. These
effects have been demonstrated in cell culture, animal feeding and healthy
volunteer studies. Fish oil decreases the host metabolic response and improves
survival to endotoxin in laboratory animals. Recently clinical studies performed
in various patient groups have indicated benefit from this approach.

Peroxisome proliferators comprise a heterogeneous group of
compounds known for their ability to cause massive proliferation of peroxisomes
and liver carcinogenesis in rodents. In recent years it has become evident that
other animals may be threatened by peroxisome proliferators, in particular
aquatic organisms living in coastal and estuarine areas. These animals are
exposed to a variety of pollutants of industrial, agricultural and urban origin
which are potential peroxisome proliferators. Both laboratory and field studies
have shown that phthalate ester plasticizers, PAHs and oil derivatives, PCBs,
certain pesticides, bleached kraft pulp and paper mill effluents, alkylphenols
and estrogens provoke peroxisome proliferation in different fish or bivalve
mollusc species. The response appears to be mediated by peroxisome-proliferator
activated receptors, members of the nuclear receptor family, recently cloned in
fish. Based on these results it is proposed that peroxisome proliferation could
be used as a biomarker of exposure to a variety of pollutants in environmental
pollution assessment. This is illustrated by a case study in which mussels, used
worldwide as sentinels of environmental pollution, were transplanted from
reference to contaminated areas and vice versa. In mussels native to an area
polluted with PAHs and PCBs, peroxisomal acyl-CoA oxidase (AOX) activity and
peroxisomal volume density were 2-3 fold and 5-fold higher, respectively,
compared to the reference site. When animals were transplanted to the polluted
station, with increased concentration of organic xenobiotics, a concomitant
significant increase of AOX was recorded. Conversely, in animals transplanted to
the cleaner station, AOX activity and peroxisomal volume density decreased
significantly. These results indicate that peroxisome proliferation is a rapid
(i.e., two days) and reversible response to pollution in mussels. Before
peroxisome proliferation can be implemented as a biomarker in biomonitoring
programs, a well-defined protocol should be established and validated in
intercalibration and quality assurance programmes. Furthermore, the influence of
biotic and abiotic factors, some of which are known to affect peroxisome
proliferation (season, tide level, interpopulation and interindividual
variability), should be taken into consideration. The possible
hepatocarcinogenic effects as well as the potential adverse effects on
reproduction, development, and growth of peroxisome proliferators are unknown in
aquatic organisms, thus providing a challenge for future investigations.

The clinical implications of the metabolism of the 2
essential fatty acids, linoleic and alpha-linolenic acid, are most clearly
related to the membrane phospholipid concentrations of their elongation and
desaturation products, arachidonic, eicosapentaenoic, and docosahexaenoic acid.
Levels of these very long chain polyunsaturated fatty acids can be altered by
diet, prematurity, and disease which can affect growth (nutritional repletion)
and the intensity and character of systemic inflammation as well as cognitive
and visual function in infants.

Fatty acids are an important source of energy which can have
an influence on serum lipids. Omega-3 and omega-6 fatty acids, both
polyunsaturated fatty acids, have been advocated as replacement for saturated
fat. Omega-3 fatty acids, derived from fish and certain green plants, lower
serum triglycerides, but they have also been shown to have a direct effect on
myocardial contractility, blood pressure, platelet function, coagulation
factors, cell-mediated immunity and markers of inflammation. Recently available
clinical trial data, including those using the concentrated omega-3 fatty acid
preparation Omacor, indicate that omega-3 fatty acids are valuable in preventing
sudden death following myocardial infarction. Studies indicate that omega-3
fatty acids are just as effective as, or have a benefit superior to, statins in
secondary prevention. Omacor is also useful in the treatment of
hypertriglyceridaemia, both as monotherapy and in combination with statins.

Nutritional interventions may favourably regulate
dyslipoproteinemia and, hence, decrease cardiovascular disease risk. Lipoprotein
kinetic studies afford a powerful approach to understanding and defining the
mechanisms by which such interventions modulate lipoprotein metabolism. Stable
isotope tracers and compartment models are now commonly employed for such
studies. We review the recent application of tracer methodologies to the study
of dyslipoproteinemia in the metabolic syndrome. We also focus on the effects of
nutritional intervention studies that have addressed the effects of weight loss,
n-3 fatty acids, plant sterols and alcohol on very low density lipoprotein, LDL
and HDL metabolism. The potential for statin treatment as an adjunct to dietary
modification is also discussed. New tracer methodologies are discussed,
specifically those referring to reverse cholesterol transport. The nutritional
interventions discussed in this review are readily transferable into clinical
preventive practice. The potential benefits to be gained by weight loss and fish
oil supplementation in the metabolic syndrome extend beyond their specific and
positive effects on lipoprotein metabolism. Furthermore, recent developments in
tracer methodologies afford new tools for probing the in-vivo pathways of
lipoprotein metabolism in future studies.

Dyslipidaemia is more frequent in solid organ transplant
recipients than in the general population, primarily as a result of
immunosuppressive drug treatment. Both cyclosporin and corticosteroids are
associated with dyslipidaemic adverse effects. In order to reduce the overall
cardiovascular risk in these patients, lipid-lowering drugs have become widely
used, especially HMG-CoA reductase inhibitors (statins). Cyclosporin, as well as
most statins (lovastatin, simvastatin, atorvastatin and pravastatin) are
metabolised by cytochrome P450 (CYP)3A4, so a bilateral pharmacokinetic
interaction between these drugs is theoretically possible. However, results from
several studies show that statins do not induce increased systemic exposure of
cyclosporin. A small (but not clinically relevant) reduction in systemic
exposure of cyclosporin has actually been shown in many studies. Cyclosporin-treated
patients on the other hand show several-fold higher systemic exposure of all
statins, both those that are metabolised by CYP3A4 and fluvastatin (metabolised
by CYP2C9). Therefore, the mechanism for this interaction does not seem to be
solely caused by inhibition of CYP3A4 metabolism, but it is probably also a
result of inhibition of statin-transport in the liver, at least in part. Other
lipid-lowering drugs, such as fibric acid derivatives, bile acid sequestrants,
probucol, fish oils and orlistat are also used in solid organ transplant
recipients. Most of them do not interact with cyclosporin, but there are reports
indicating that both probucol and orlistat may reduce cyclosporin
bioavailablility to a clinically relevant degree. There is no information on
possible interaction effects of cyclosporin on the pharmacokinetics of
lipid-lowering drugs other than statins, but it is not likely that any clinical
relevant interference exists with fish oil, orlistat, probucol or bile acid
sequestrants.

A great amount of evidence from epidemiological studies and
clinical trials supports a protective effect against coronary heart disease for
fish consumption and intake of marine omega-3 fatty acids. Biological pathways
for this risk reduction include membrane stabilization in the cardiac myocite,
inhibition of platelet aggregation, favourable modifications of the lipid
profile, decrease in blood pressure and reduction of the inflammatory response
of the endothelium. Results from epidemiological studies suggest a threshold
effect for the consumption of fish and omega-3 fatty acids. Risk reduction is
especially important for cardiac sudden death. Nevertheless, protection against
non-fatal coronary heart disease has also been observed. Recently published
studies have shown that mercury intake, present in high concentrations in fish,
could counteract the beneficial effect from fish consumption.